“Unveiling a Novel Therapeutic Approach for the Treatment of Alzheimer’s Disease”

2023-04-27 Academic

Research team at the College of Pharmacy has developed a new compound that can induce selective degradation of proteins involved in Alzheimer’s disease

A research team led by Professors Nam-Jung Kim, Jong Kil Lee, and Kyung-Soo Inn of the College of Pharmacy developed PRZ-18002, a new compound that can inhibit the symptoms of disease by selectively degrading phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK), which plays a pivotal role in the pathophysiology of Alzheimer's disease (AD). The research team administered PRZ-18002 to the nasal cavity of mice model of AD and confirmed the improvement of its spatial learning and memory. The research results were published in ACS Central Science (IF=18.728), an internationally renowned academic journal in the field of chemistry, under the title, “Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimer's Disease.”

Alzheimer's disease is one of the most common degenerative brain diseases and a leading cause of dementia. It imposes great suffering on patients, their families, and society, accompanied by cognitive dysfunction and mental-behavioral abnormalities. The exact cause of this disease is not known, but it has been suggested that the pathogenetic mechanism of the disease hinges on a protein called beta-amyloid which can, when produced excessively, be deposited in the brain, affecting brain cells. In addition, intracellular deposition of tau protein, inflammatory response, and oxidative damage are also known to cause brain cell damage and affect the onset of Alzheimer's disease.

Binds to and destroys AD-causing protein
“p38 MAPK” is a type of enzyme involved in cell development, activated by pro-inflammatory cytokines and environmental stress. Activation of cytokines is known as a major exacerbation mechanism of various chronic inflammatory diseases, and many studies have been done for a long time. In particular, beta amyloid and tau protein, which are the main factors of AD, have recently been identified as key factors for the activation of these proteins, and chronic inflammation is also reported to be closely related to AD. Numerous candidates targeting cytokines have been developed over the past decades, but none has emerged as a new drug.

The research team theorized that developing a compound that could selectively bind to and destroy phosphorylated p38 MAPK (p-p38 MAPK) would overcome the limitations of existing drugs. However, at that time there was no known case of proteins that had undergone post-translational modification such as phosphorylation could be selectively degraded. The research team used a Targeted Protein Degradation (TPD) strategy to synthesize a series of p-p38-degrading small molecules, selectively targeting only p-p38 MAPK for the first time in the world, to maximize the therapeutic effect of the drug. The second compound of the series PRZ-1800 proved to be most effective with excellent kinase selectivity, which was subsequently named “PRZ-18002.”

The targeted proteolysis strategy has been one of the most significant strategies in the field of innovative pharmacological development since the strategy concept was demonstrated in 2015. Existing small-molecular chemical drugs simply bind to the protein that causes the disease and suppress the activity and function of the protein. This modality had a limitation in that the drug could not exert its effect when the binding with the protein was dissolved. Drugs developed with targeted proteolysis strategies, however, can permanently remove the pathogenetic protein and demonstrates strong pharmacological effectiveness.

The research team underwent biochemical tests of PRZ-18002. Through this, it was confirmed that only the phosphorylated p38 MAPK was selectively removed, and a strong anti-inflammatory effect was confirmed at the cellular level. PRZ-18002 was administered to AD mice model (5xFAD), and as a result, it was confirmed that the levels of p-p38 MAPK were reduced in the cortex and hippocampus of the mice. Spatial perception ability was also evaluated through behavioral evaluation experiments, and memory and cognition improvement effects were also found. PRZ-18002 also reduced beta amyloid plaque deposition, cortical and hippocampal beta amyloid levels, and reduced some neuroinflammatory markers in mice. Through the experimental results, the research team confirmed that PRZ-18002 could be a candidate for a new treatment for AD.

Entrepreneurship is a new impetus for research, follow-up research to overcome the shortcomings of targeted protein degradation strategies
Professor Nam-Jung Kim said, “ACS Central Science, in which the research results were published, is a prestigious academic journal by the American Chemical Society with Professor Carolyn R. Bertozzi, who is the 2022 Nobel laureate for chemistry, as the editor-in-chief. I am personally very pleased to be able to share my research results with scientists in related fields around the world.”

Professors Kim, Lee, and Inn, who jointly led the research team, also worked together as the research team that founded Prazer Therapeutics, an innovative new drug development company based on proteolysis technology, in 2019. On the positive impact of entrepreneurship on his research, Professor Kim explained, “Founding a startup company created a virtuous cycle structure in research. After starting the business, I established a research center as an investment, and the research results from this center also inspire me to do further research, both on and off-campus. Most of the researchers at the center are our former students. As researchers continue to carry out research in the continuity of the research they did during their degree period, their expertise in the field is increasing. These are the advantages as an example of industry-university cooperation.”

“New drug development” is the goal for Professor Kim, both as a researcher and an entrepreneur. He explained why he set the goal of developing a new drug, saying, "I hope that, at the end of my life, I might be assured that some of my research achievements have had an impact in saving people’s lives.” The current research result is a new beginning for him. He added, “While diverse targeted protein degradation methods have recently emerged, there are also limitations in many cases in terms of drug properties such as restrictions on oral administration. We are conducting research to find a way to solve this problem, and further research is already underway with an improved methodology of development.”

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